tbuckley/cabot-search huggingface dataset:
Impact of pre-treatment hemoglobin (Hgb) on outcomes in metastatic castration resistant prostate cancer (mCRPC) with lutetium-177-PSMA-617 (Lu-177).
Authors: Ariel Ann Nelson, Kristin Riemersma, Kathryn A. Bylow, Michael Holt, Deepak Kilari
Journal: Journal of Clinical Oncology (2023)

e17065 Background: The Phase 3 VISION and TheraP trials excluded men with Hgb≤ 9 g/dL or blood transfusion within 30 days of Lu-177. Patients (pts) with mCRPC who are eligible for Lu-177 are often pancytopenic due to marrow infiltration and previous cytotoxic therapy. Clinicians are often faced with the dilemma of packed red blood cell (RBC) transfusion (Tx) to meet “eligibility requirements" of Lu-177. The impact of low Hgb levels on treatment (trt) outcomes is unclear. Methods: We retrospectively identified pts with mCRPC who received at least one cycle of Lu-177 between July 2022 and January 2023 at a single institution. Demographic, disease, laboratory and trt characteristics were recorded. Pts with Hgb level ≤10 g/dL or who received RBC Tx up to 14 days prior to the first Lu-177 dose were compared to pts with a pre-trt Hgb level ≥10 g/dL and no prior PRBC Tx. Data were summarized using descriptive statistics. Time to trt discontinuation was defined as the time from the first Lu-177 cycle until progressive disease per treating physician (clinical, radiographic, PSA progression) or adverse effect necessitating cessation and compared using the Kaplan Meier method. Cox proportional hazard regression analysis were utilized to assess the association of Hgb ≤ or ≥ 10 g/dL on the risk of trt discontinuation. Results: 51 pts were included, median follow up was 5.75 months, median age 70 years, 90% Caucasian. 49% (n = 25) had Gleason 9 /10 disease. Median number of prior trt was 4. 94% (n = 48), received prior docetaxel and 39% (n = 20) received prior cabazitaxel. 27% (n = 14) of pts had either Hgb≤10 or received a RBC Tx prior to trt. Of these, 50% of pts (n = 7) had stopped Lu-177 prior to completion of 6 cycles. Median number of cycles was 3. Reasons for trt cessation included clinical decline (n = 4), PSA or radiographic disease progression (n = 2), cytopenia (n = 1). Of pts who had Hgb ≥10 (n = 37), most (86%) are in ongoing trt, 11% (n = 4) have stopped trt due to progressive disease, 1 pt died. Pts with Hgb≤10 had a shorter time to trt discontinuation, 4.5 months (95% CI: 4.43- NA) vs not reached for those with Hgb≥10, p = 0.004 and an increased risk of trt discontinuation HR = 1.65 (95% CI: 1.53-18.09, p = 0.009). Conclusions: Pre-trt Hgb≤10 g/dL may be associated with worse outcomes in pts with mCRPC undergoing trt with Lu-177 and caution should be exercised. A larger data set and longer follow up is needed to further investigate outcomes in this pt population. Multivariable analysis is planned. [Table: see text]
The effect of a reduced dose of enzalutamide on fatigue and cognition.
Authors: Joanneke Overbeek, Emmy Boerrigter, Guillemette Emma Benoist, Diederik Meindert Somford, Paul Hamberg, Jolien Tol, Brian Scholtes, Annelieke E.C.A.B. Willemsen, Laurien M Buffart, Roy P.C. Kessels, Niven Mehra, Inge M. van Oort, Nielka P. Van Erp
Journal: Journal of Clinical Oncology (2023)

5051 Background: Enzalutamide (ENZA) is a highly effective treatment for patients (pts) with metastatic prostate cancer, but central nervous system (CNS)-associated side effects occur frequently and may hamper the quality of life. These side effects are addressed with dose reductions, while they potentially can be prevented by starting at a reduced dose, since androgen receptor saturation is already observed at dose levels above 60 mg once daily (OD) and ENZA plasma concentrations &gt; 5 mg/L. We hypothesized that a lower starting dose of ENZA can reduce the risk of CNS side effects in frail pts while preserving efficacy. In this study (NCT03927391) the effect of a reduced dose of ENZA on fatigue and cognitive side effects is determined. Methods: This randomized multi-center trial compared the ENZA standard dose of 160 mg OD to the reduced dose of 120 mg OD in frail prostate cancer pts. At baseline, and 6, 12, and 24 weeks after start of ENZA, fatigue and cognitive side effects were measured by the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) and Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) questionnaires. A change in scores of 3.0 for the FACIT-F and 7.0 for the FACT-Cog was considered clinically relevant. Linear mixed effects models were used to study within and between-group differences in fatigue and cognitive side effects over time. Furthermore, ENZA plasma concentrations were measured after 6, 12, and 24 weeks of treatment and PSA response (&gt;50% PSA decline) was compared between the two dosing regimens. Results: A total of 51 pts were included (25 reduced dose, 26 standard dose). Completion rates for the questionnaires were high throughout the study (&gt;90%). Pts treated at the reduced dose showed no significant changes in FACIT-F and FACT-Cog scores over time. Pts treated at the standard dose showed increasingly worse FACIT-F and FACT-Cog scores. This resulted in clinically relevant and statistically significant better FACIT-F and FACT-Cog scores for pts treated at the reduced dose compared to pts treated at the standard dose after 24 weeks (table). All pts had therapeutic ENZA concentrations (&gt;5 mg/L) throughout the study. PSA response did not differ between both groups (87% for 120mg OD vs 80% for 160mg OD, p=0.796). Conclusions: By starting with a reduced dose of ENZA of 120mg OD CNS side effects can be prevented, which might beneficially affect the quality of life of frail prostate cancer pts, without any indication of interference with efficacy endpoints. Clinical trial information: NCT03927391 . [Table: see text]
Fruquintinib versus fruquintinib combined with PD-1 inhibitors for metastatic colorectal cancer: Real-world data.
Authors: Lina He, Xiaojiao Cheng, Shuiping Tu
Journal: Journal of Clinical Oncology (2023)

e15592 Background: The treatment in patients with metastatic colorectal cancer (mCRC) have limited effectiveness and options. And research findings have revealed that combining anti-angiogenesis inhibitors with programmed death-1(PD-1) inhibitors can reverse the immunosuppressive tumor microenvironment and synergistically enhance the antitumor immune response. The goal of the study was to add more real-world data to prove the clinical efficacy and safety of this regimen. Methods: We conducted a Real-World observation study by comparison of the efficacy and safety of fruquintinib versus fruquintinib combined with PD-1 inhibitor in patients with mCRC who received treatment between June 2019 and October 2022 in our center. Results: A total of 106 patients with mCRC were observed to receive fruquintinib(F group) (n = 26, mean age = 63 years, female = 46.2%) or fruquintinib combined with PD-1 inhibitor (FP group)(n = 80, mean age = 62 years, female = 46.3%). 3.8% of patients achieved partial response (PR) in FP group and 47.5% had stable disease (SD). Of the F group, no patient had PR and SD was 50%. No difference was found for median progression-free survival(PFS) (F group 6.7 months vs. FP group 4.5 months, p = 0.271). Median overall survival(OS) was significantly prolonged with F group compared with FP group (18.7 months vs. 13.6 months, p = 0.008), which was mainly attributed to the disease course before the treatment of fruquintinib or fruquintinib combined with PD-1 inhibitor in the two groups (42.9 months vs. 31.8 months, p = 0.031). And univariate Cox regression analysis showed that clinical factors (Stage at first diagnosis, PD-L1 gene, number of organs with metastases, and operative treatment) were associated with OS in the FP group (p &lt; 0.05), while only PD-L1 gene positive had significant difference in multivariate analysis (p = 0.024). In the F group, no factors had a significant impact on OS in Cox analysis. Further analysis on immune indices in the FP group indicated that total-MDSCs and PMN-MDSCs significantly decreased after treatment (p = 0.039), mainly resulting from the PR/SD subgroup (p = 0.019) rather than the PD subgroup (p = 1.000). Most adverse events occurred between these two groups were very similar, while any grade of myelosuppression, hepatic injury, abdominal pain, palmar-plantar erythrodysesthesia and hypothyroidism were more frequently observed in the FP group and≥grade 3 myelosuppression was more common. Conclusions: Among patients with metastatic CRC, fruquintinib combined with PD-1 inhibitor couldn't significantly prolong PFS and OS compared with only fruquintinib therapy, but could made a few patients partial response. Total/PMN-MDSCs may be an important indicator of the efficacy of the combined therapy. The combined treatment increased more side effects, yet showed an acceptable safety profile.
Tandem duplicator phenotype: A novel targetable subgroup in pancreatic cancer?
Authors: Abdul Rehman Farooq, Amy Zhang, Grainne M. O'Kane, Robert Edward Denroche, Gun Ho Jang, Sandra Fischer, Anna Dodd, Spring Holter, Julie Wilson, Robert C. Grant, Kyaw Lwin Aung, George Zogopoulos, Elena Elimova, Rebecca M. Prince, Raymond Woo-Jun Jang, James Joseph Biagi, Faiyaz Notta, Steven Gallinger, Jennifer J. Knox, Erica S Tsang
Journal: Journal of Clinical Oncology (2023)

4161 Background: Validated biomarkers are urgently needed to provide a more precise approach in pancreatic cancer (PDAC). Homologous recombination deficiency (HRD) is a heterogenous cohort in PDAC and predicts platinum and PARP inhibitor sensitivity. The BRCA-1 genotype associates with distinct tandem duplications (TDs), however non-BRCA 1 TD phenotypes (TDP) have been observed across tumour types and may be associated with perturbations in CDK12, FBXW17, and CCNE1. Here, we characterize the prevalence and outcomes of TDP in a large series of prospectively sequenced PDAC. Methods: Whole-genome sequencing was performed in 191 early stage resected and 275 advanced PDAC cases in the PanCuRx initiative and the COMPASS trial at the Ontario Institute for Cancer Research and Princess Margaret Cancer Centre. Tumors underwent laser capture enrichment prior to sequencing. TD scores were calculated as previously described by Menghi et al, and HRDetect scores assigned. Samples were classified as classical or basal-like by Moffitt. Outcomes of patients with TDP tumors were evaluated. Tumors that are nonHRD and nonTDP are referred to as typicals. Results: Of 466 cases, 46 were identified as TDP (9.9%; 17 resected, 29 advanced). Subgroups of TDP by etiology included BRCA1 (n=8; 6 germline, 2 somatic), somatic CCNE1 (n=1), and unknown (n=37; no identified alterations in TDP-related genes). Pathogenic germline variants were not found in unique genes other than BRCA1. HRD TDP was associated with a significantly smaller TD size compared to nonHRD TDP (median 12 kb vs. 125 kb, p&lt;0.0001) and median TD load of 114. NonHRD TDP genomes exhibited elevated TD load (median 70 vs. 13, p&lt;0.0001) and HRDetect scores (p&lt;0.0001) compared with typicals. NonHRD TDP was not prognostic in resected PDAC disease (p=0.6361) compared with typicals. We observed a trend towards improved response to 1st-line platinum therapy in nonHRD TDP vs. typicals (p=0.066) for patients with advanced disease. When stratified for only ‘classical’ RNA subtype cases as per Moffitt classification (HRD TDP:2 basal-like, 8 classical, 1 unknown; nonHRD TDP: 9 basal-like, 25 classical, 1 unknown), platinum therapy was correlated with better response in non-HRD TDP vs. typicals (n= 10, 70% ORR, p=0.0108) highlighting the chemoresistance of the basal-like subgroup. Superior survival was not observed in this small cohort. Conclusions: In PDAC, the etiology of nonHRD TDP is unclear but may represent a potential marker for platinum and DNA damage response agents. Further investigation is warranted with a larger sample size.
Prognostic significance of pretreatment immune cell infiltration in muscle invasive bladder cancer treated with definitive chemoradiation: Analysis of NRG RTOG 0524 and 0712.
Authors: Matthew Pierre Deek, Amol Shetty, Yang Song, Jason A. Efstathiou, Felix Y Feng, William U. Shipley, Jeff Simko, Kent William Mouw, David Tomoaki Miyamoto, Alan Pollack, Dror Dror Michaelson, Anthony L. Zietman, John Coen, Douglas M. Dahl, Ashesh B. Jani, Luis Souhami, Brian K. Chang, R. Jeffrey Lee, Stephanie L. Pugh, Phuoc T. Tran
Journal: Journal of Clinical Oncology (2023)

4523 Background: Chemoradiation therapy (CRT) is an organ conserving approach in the treatment of locally advanced bladder cancer. Chemoradiation is thought to potentially result in immunogenic stimulation, and bladder cancer is often a tumor with high immune cell infiltration. Thus, we aimed to profile the tumor immune microenvironment of bladder cancer and identify prognostic immune biomarkers for CRT response by profiling tumor samples from NRG/RTOG 0524 and 0712, two prospective trials of CRT in muscle invasive bladder cancer (MIBC). Methods: Pretreatment tissue samples from both trials were profiled using Cofactor Genomics ImmunoPrism, an RNA sequencing assay that uses gene expression profiles to quantify immune cell populations in the tumor microenvironment (TME). Differential gene expression was estimated for different immune cell type proportions across samples. Kaplan-Meier survival analysis and log rank tests were performed to evaluate differences in overall survival (OS) stratified by genes influenced by immune cell proportions or genes associated with immune response signatures. Results: A total of 70 samples (43 from RTOG 0524 and 27 from RTOG 0712) underwent analysis using the ImmunoPrism assay. Immune cell proportions were as follows: CD8 T cells: median 1.2%, CD4 T cells: median 0.8%, Treg cells: median 9.2%, CD19 B cells: median 5.1%, M2 macrophages: median 0.8%, M1 macrophages: median 0%. Unbiased clustering based on gene expression profiles driven by immune cell proportions demonstrated two groups: cluster 1 with a low percentage of immune cells and shorter OS (median 31 months) and cluster 2 with a high percentage of immune cells and longer OS (median 101 months, p = 0.036). Higher expression of genes associated with T cell infiltration ( CD8A and ICOS) was associated with improved OS (104 vs 35 months, p = 0.028, HR = 0.48 (0.25 – 0.94), p = 0.031) as was higher expression of IDO1, which is associated with the interferon gamma pathway (104 vs 35 months, p = 0.042, HR = 0.49 (0.24 – 0.99), p = 0.046). Conclusions: Bladder tumors have a wide range of immune cell infiltration in the TME. Increased immune cell proportions are prognostic for OS following CRT, as well as a higher expression of genes associated with T cell infiltration interferon gamma signaling. These findings have implications for the integration of immunotherapy in the definitive management of MIBC; and can be explored further in the ongoing NRG/SWOG 1806 trial.
The broader impact of specialized outpatient cancer rehabilitation on health and quality of life among breast cancer survivors.
Authors: Mackenzi Pergolotti, Kelley C Wood, Tiffany Kendig
Journal: Journal of Clinical Oncology (2023)

e18881 Background: After diagnosis and treatment, women with cancer often experience significant functional decline from which most do not recover. Functional deficits, especially when persistent, are related to poorer health and quality of life (QOL). Interventions to mitigate declines in function, health and QOL are necessary given their known associations with morbidity and mortality yet are understudied and underutilized. While there is evidence supporting cancer rehabilitation’s (Physical or Occupational therapy, PT/OT) ability to improve physical function and upper extremity disability among breast cancer survivors (BCS), the impact of cancer PT or OT on health and QOL is unknown. To understand this broader impact, we examined the rehabilitation needs and outcomes of BCS who attended specialized, community-based cancer PT/OT. Methods: In this retrospective study, we extracted case characteristics and patient-reported outcomes (PRO) measures of health, function and QOL from a national sample of BCS who attended cancer-specialized outpatient PT or OT. We examined ICD-10 codes to identify rehabilitation needs. PROs collected at baseline and discharge from rehabilitation included: Patient Reported Outcome Measuring System (PROMIS) global physical health, global mental health, physical function, and ability to participate in social roles and activities. To examine change from baseline to discharge we used paired t-tests ( p&lt; .05) and calculated effect size (Cohen’s d). Results: PT/OT patients (N = 2,706; PT, n = 2,245; OT, n = 461) were 99.6% female, 58.33±12.50 years old and attended approximately 10 (IQR: 7.0 – 17.0) sessions. Needs included: muscle atrophy, weakness or ataxia (PT: 44%, OT: 32%); lymphedema (PT: 40%, OT: 56%); upper extremity impairment (PT: 44%, OT: 28%); pain (PT: 44%, OT: 25%); and scar tissue or fibrosis (PT: 15%, OT: 16%). At discharge, all health, function and QOL-related outcomes improved significantly (p &lt; .001) in both PT and OT. Specifically, significant gains in PROMIS global physical health (PT: M∆ = 3.56±7.21, d= 0.49; OT: M∆ = 2.26±7.03, d= 0.32), global mental health (PT: M∆ = 2.01±6.91, d= 0.29; OT: M∆ = 1.34±7.20, d= 0.19), physical function (PT: M∆ = 2.81±7.45, d= .38, M∆ = 1.91±7.39, d= .26), and participation in social roles &amp; activities (PT: M∆ = 3.24±9.09, d= .36; OT: M∆ = 1.91±8.41, d= .23) were observed. Conclusions: BCS presented to community-based outpatient rehabilitation with a variety of needs yet, despite this variety, demonstrated significant improvement in self-perceived health, physical function and QOL. Significant gains were reported for both PT and OT interventions. For providers working with BCS, these results can be used to increase awareness of the role of cancer rehabilitation and support referral to these services. Future research should evaluate the impact of specialized PT/OT on individuals with other cancer types.
Regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma efficacy and safety of patients: A real-world study.
Authors: Yi Bai, Jianfa Yu, Chuanliang Cheng, Dapeng Chen, Yamin Zhang
Journal: Journal of Clinical Oncology (2023)

e16126 Background: Results from the RESORCE-III RCT demonstrated that sequential sorafenib-regorafenib treatment significantly improved overall survival compared with the placebo group. However, there are no retrospective studies of regorafenib as a first-line agent for treating patients with advanced hepatocellular carcinoma in a real-world setting. Therefore, we aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with immune checkpoint inhibitors (ICIs) in treating patients with advanced hepatocellular carcinoma in a real-world setting. Methods: We reviewed medical data from 48 patients with advanced hepatocellular carcinoma treated with regorafenib as a first-line agent alone or combined with ICIs between December 2018 and February 2022. These patients were treated with regorafenib for at least 28 consecutive days (21 days on and 7 days off the drug). The progression-free survival (PFS), overall survival (OS), objective response rate (ORR, RECIST 1.1 criteria) and disease control rate (DCR) were observed. Results: A total of 48 patients were enrolled in this study, 26(54.2%) receiving regorafenib as monotherapy and 22(45.8%) receiving the combination ICIs. The median age in the monotherapy group was 54 years (range 38-74), male/female (69.2%/30.8%), BCLC stage B/C (42.3%/57.7%), Child-Pugh A/B score (57.7%/42.3%); the median age in the combined ICIs group was 53 years (range 42-75), male/female (68.2%/ 31.8%), BCLC stage B/C (36.4%/63.6%), Child-Pugh A/B score (54.5%/45.5%). Median PFS (mPFS) was 7.7 months (95% CI:5.9-10.4) and median OS (mOS) was 16.7 months (95% CI:14.3-23.6) in 48 patients. In the regorafenib monotherapy group, mPFS was 5.9 months (95% CI:5.6-10.3) and mOS was 13.9 months (95% CI:13.5-22.5); in the combined ICIs group, mPFS was 7.8 months (95% CI:7.3-14.5) and mOS was 23.6 months (95% CI:16.6-NA). The ORR and DCR were 20.8% and 72.9% in the overall treatment group, 15.4% and 65.4% in the monotherapy group, and 27.3% and 81.8% in the combined ICIs treatment group, respectively. Among the adverse events, rates were 34.6% (9/26) and 36.4% (8/22) in the monotherapy and combined ICIs groups, respectively, with only one grade III/IV adverse event in the monotherapy group and no grade III/IV adverse event in the combined ICIs group. Conclusions: This retrospective, real-world, preliminary study demonstrates that regorafenib as a first-line agent alone or in combination with ICIs has a high safety profile and more prolonged survival in patients with advanced hepatocellular carcinoma, particularly in combination with ICIs.
Phase 1/2a study of PRL-02, a long-acting intramuscular (IM) depot injection of abiraterone decanoate, in patients (pts) with advanced prostate cancer.
Authors: Neal D. Shore, Jose W. Avitia, James L. Bailen, Luke T. Nordquist, William Richardson, Cody J. Peer, William Douglas Figg, Jacqueline M. Walling, Joel Robert Eisner, Matthew Sharp, Robert J. Schotzinger, William R. Moore, Ronald F. Tutrone
Journal: Journal of Clinical Oncology (2023)

TPS5117 Background: PRL-02 is a long-acting IM depot injection of abiraterone decanoate, a novel prodrug of abiraterone delivered through the lymphatic system. PRL-02 potently blocks androgen production with minimal increases in mineralocorticoids or decreases in glucocorticoids through preferential inhibition of Cytochrome P450 (CYP)17 lyase versus CYP17 hydroxylase. Phase 1 is a standard 3+3 design intended to identify a recommended Phase 2 dose (RP2D). PRL-02 is administered every 84 days (1 cycle). As of 9/8/22, 17 pts (6 mCRPC, 11 mCSPC) were treated across 5 dose cohorts (180, 360, 720, 1260, 1800mg). At 720mg and above, 9 of 11 had a 90% reduction in testosterone (T), including 2 pts with T≤ Lower Limit of Quantitation (LLOQ) of 0.1ng/dL. A PSA decline of ≥50% from baseline (PSA50) was observed in 8 of 10pts. PRL-02 was very well tolerated. Only minimal and transient changes in ‘upstream’ steroids (e.g., progesterone) were observed at doses of 1260 mg (the RP2D) and lower. Methods: Phase 2a is an A'Hern single-stage design. Group 1 includes pts with mCSPC divided into 2 groups (1A: previously untreated high-volume disease and 1B: previously untreated, low-volume disease). Group 2 includes pts with mCRPC. Enrollment of 66 pts is planned across 30 sites in the U.S. (NCT04729114). Patient populations, interventions and study design are described below. Clinical trial information: Clinical Trial information: NCT04729114 . [Table: see text]